1-(4-Alkyl-2-aryl-1,3-dioxolan-2-ylmethyl)-1H-imidazoles

ABSTRACT

Novel 1-(4-alkyl-2-aryl-1,3-dioxolan-2-ylmethyl)-1H-imidazoles useful as antifungal and antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of my copending application, Ser. No.619,863, filed Oct. 6, 1975, now abandoned, which in turn is acontinuation-in-part of my application Ser. No. 544,157, filed Jan. 27,1975, now issued as U.S. Pat. No. 3,936,470.

PRIOR ART

In U.S. Pat. Nos. 3,575,999 and 3,717,655 are described some1-(2-aryl-1,3-dioxolan-2-ylmethyl)imidazoles. The compounds of thisinvention differ from the foregoing essentially by the nature of thealkyl substituent, present in the 4-position of the dioxolane group.

DESCRIPTION OF THE INVENTION

The invention relates to novel1-(4-alkyl-2-aryl-2-ylmethyl)-1H-imidazoles having the formula: ##STR1##and the therapeutically acceptable acid addition salts thereof, wherein:R is alkyl having from 2 to about 10 carbon atoms; and

Ar is a member selected from the group consisting of phenyl, substitutedphenyl, thienyl, halothienyl and naphthalenyl, and wherein saidsubstituted phenyl is phenyl having from 1 to 3 substituentsindependently selected from the group consisting of halo, lower alkyl,lower alkyloxy, nitro and cyano.

More particularly "alkyl" as used in the definition of R is meant toinclude straight and branch chained hydrocarbon radicals having from 2to about 10 carbon atoms, such as, for example, ethyl, propyl,1-methylethyl, 1,1-dimethylethyl, butyl, pentyl, hexyl, heptyl, octyl,decyl and the like alkyls; "lower alkyl" as used herein has the meaningof a straight or branch chained alkyl radical having from 1 to about 6carbon atoms, such as, for example, methyl, ethyl, propyl,1-methylethyl, 1,1-dimethylethyl, butyl, pentyl, hexyl and the likealkyls; and the term "halo" is generic to halogens of atomic weight lessthan 127, i.e., fluoro, chloro, bromo and iodo.

The compounds of formula (I) are conveniently prepared by reactingimidazole (II) with an appropriate reactive ester of formula (III)wherein Ar and R are as previously defined and wherein W is a reactiveester function, such as, for example, halo, 4-methylbenzenesulfonate,methanesulfonate and the like. Preferred reactive esters are halides andmore particularly bromides and chlorides.

In one method of conducting the reaction between imidazole and (III),imidazole is first transformed into a metal salt thereof by treatmentwith an appropriate metallating agent such as, for example, a metalalkoxide, e.g., sodium- or potassium methanolate, or a metal hydridesuch as sodium hydride. The thus obtained metal salt is then reactedwith (III) in an appropriate organic solvent, such as, for example,dimethylformamide or dimethylacetamide. A small amount of a metaliodide, such as sodium or potassium iodide may advantageously be addedto promote the reaction, especially when the reactive ester is achloride or bromide.

Alternatively, the reaction of imidazole with the reactive ester (III)may also be carried out without previous salt formation, by bringing thereactants into contact with each other in an appropriate organic solventsuch as, for example, dimethylformamide or dimethylacetamide. In thesecircumstances it is appropriate to use an excess of imidazole or to addto the reaction mixture an appropriate base such as, for example, sodiumor potassium carbonate or bicarbonate in order to bind the acid which isliberated during the course of the reaction. The use of an excess ofimidazole is however preferred. Further it is advantageous to conductthe reaction in the presence of a metal iodide such as, for example,sodium or potassium iodide.

In each of the above procedures, somewhat elevated temperatures may beemployed to enhance the rate of the reaction and most conveniently thereactions are carried out at the reflux temperature of the reactionmixture.

In these and the following preparations the reaction products may beisolated from the medium and, if necessary, further purified accordingto methodologies generally known in the art, such as, for example,extraction, trituration, crystallization, chromatography, etc.

The foregoing procedures are more fully illustrated by the followingschematic representation: ##STR2##

An additional method of preparing the compounds of formula (I) is by theketalization of an appropriate aroylmethylimidazole of formula (IV)wherein Ar has the same meaning as assigned to it previously with anappropriate diol of formula (V) wherein R is as previously defined.

Said ketalization reaction may be carried out following methodologiesanalogous to those described in the literature, e.g., for thepreparation of 2-bromomethyl-2,4-diphenyl-1,3-dioxolane [Synthesis, 1974(I), 23].

In a preferred manner of carrying out the reaction both reactants arerefluxed together for several hours with azeotropic water removal in anappropriate organic solvent, preferably in the presence of a simplealcohol, such as, for example, ethanol, propanol, butanol, pentanol andthe like, and in the presence of an appropriate strong acid such as4-methylbenzenesulfonic acid. Suitable organic solvents are, forexample, aromatic hydrocarbons, such as benzene, methylbenzene,dimethylbenzene and the like and saturated hydrocarbons, such ascyclohexane.

The foregoing reaction may be illustrated as follows: ##STR3##

The imidazole derivatives of formula (I), obtained in base form in theforegoing preparations, may be converted to their therapeutically usefulacid addition salts by reaction with an appropriate acid, as, forexample, an inorganic acid such as hydrohalic acid, i.e., hydrochloric,hydrobromic or hydroiodic acid; sulfuric, nitric or thiocyanic acid; aphosphoric acid; an organic acid such as acetic, propanoic,hydroxyacetic, α-hydroxypropanoic, 2-oxopropanoic, ethanedioic,propanedioic, 1,4-butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxy-1,4-butanedioic, 2,3-dihydroxy-1,4-butanedioic,2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenylpropenoic,α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, 4-methylbenzenesulfonic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic, 2-phenoxybenzoic or 2-acetyloxybenzoic acid.The salts are in turn converted to the corresponding free bases in theusual manner, e.g., by reaction with alkali such as sodium or potassiumhydroxide.

The intermediates of formula (III) may be prepared by subjecting anappropriate ketone of formula (VI), wherein Ar and W are as previouslydefined to a ketalization reaction with an appropriate diol of formula(V) in the same manner as described hereinbefore for the preparation ofthe compounds (I) starting from (IV) and (V). ##STR4##

Alternatively the intermediates of formula (III) are convenientlyprepared by transketalization of a ketal derivative of a ketone offormula (VI) such as, for example, a lower alkyl ketal or a cyclic loweralkylene ketal, with a glycol of formula (V) under conditions similar tothose described hereinbefore for the direct ketalization. The loweralkyl ketals and cyclic lower alkylene ketals used herein as startingmaterials are easily obtained by ketalization of a ketone of formula(VI) with a lower alkanol or alkanediol according to methodologies knownin the art. A number of such compounds and methods of preparing the sameare described in U.S. Pat. Nos. 3,575,999 and 3,717,655.

The intermediates of formula (III) are deemed to be novel and as usefulintermediates herein they constitute an additional feature of thisinvention.

The precursor glycols of formula (V) are generally known and they mayall be prepared according to known procedures as described in theliterature.

The precursor arylketones of formula (VI) are also generally known andmay be prepared following art-known methodologies. Bromides are, forexample, easily obtained by the bromination of the corresponding methylaryl methanone with bromine.

The aroylmethyl substituted imidazoles of formula (IV), a number ofwhich are described in U.S. Pat. No. 3,717,655 are conveniently preparedby the reaction of (VI) with imidazole in an analogous manner aspreviously described for the preparation of the compounds (I) startingfrom imidazole and (III).

From formula (I) it is evident that the compounds of this invention havetwo asymmetric carbon atoms in their structures, namely those located inthe 2- and 4-position of the dioxolane nucleus, and consequently theyexist under different stereochemical optical isomeric forms. Thestereochemical optical isomeric forms of (I) and the therapeuticallyactive acid addition salts thereof are intended to be within the scopeof this invention.

The diastereomeric racemates of (I), denoted as cis and trans formsrespectively, according to the rules described in "Naming and Indexingof Chemical Substances for Chemical Abstracts during the 9th CollectivePeriod (1972-1976)", published in C.A. 1972, 76, Index Guide Section IV,p. 85, may be obtained separately by conventional methods. Appropriatemethods which may advantageously be employed therefore include, forexample, selective crystallization and column-chromatography. For anumber of compounds the stereochemical configuration was experimentallydetermined. In the remaining cases it is conventionally agreed todesignate the stereochemical form which is first isolated as "A" and thesecond as "B", without further reference to the actual stereochemicalconfiguration.

Since the asymmetric carbon atoms are already present in theintermediates (III) it is also possible to separate cis and trans forms,or generally "A" and "B" forms at this stage, whereupon thecorresponding forms of (I) may be obtained after reaction of theforegoing with imidazole as previously described. The separation of cisand trans forms of (III) may be performed by conventional methods asdescribed hereinbefore for the separation of the compounds (I) intotheir cis and trans forms.

It is evident that the cis and trans diastereomeric racemates may befurther resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of methodologies known to those skilledin the art.

The compounds of formula (I) and the acid addition salts thereof areuseful agents in combatting fungi and bacteria. As such they arevaluable in the treatment of human beings, animals and plants sufferingfrom pathogenic microorganisms and in the destruction of microorganismson materials.

The broad spectrum of antifungal and antibacterial activity of thecompounds of formula (I) is clearly illustrated by the experimental datapresented hereafter. The compounds in the tables are not listed for thepurpose of limiting the invention thereto, but only in order toexemplify the useful properties of all the compounds within the scope offormula (I).

The test for antifungal activity was performed using Sabouraud's liquidmedium in test tubes each containing 4.5 ml of liquid medium, autoclavedat 120° C. for 15 minutes. The substances were dissolved in 50% ethanolat a concentration of 20 mg/ml and subsequently diluted with steriledistilled water to a concentration of 10 mg/ml. Successive decimaldilutions were then made with distilled water to give a series of stocksolutions. To each tube containing 4.5 ml of Sabouraud's liquid mediumwas added 0.5 ml of one of the stock solutions to give a concentrationof the drug under investigation of 100 μg, 10 μg, 1 μg or 0.1 μg per mlof medium.

Filamentous fungi were incubated at 25° C. for 2-3 weeks. A square blockof side 2 mm. was excised and inoculated into the liquid medium. Athree-day old culture on Sabouraud's liquid medium was used for yeasts,and the inoculum was 0.05 ml per tube. All the cultures were incubatedat 25° C. for 14 days. The final readings were taken after two weeks andare summarized in the Tables I as follows:

    ______________________________________                                        ++++     =     complete inhibition of growth at 0.1 μg/ml                  +++      =     complete inhibition of growth at 1 μg/ml                    ++       =     complete inhibition of growth at 10 μg/ml                   +        =     complete inhibiton of growth at 100 μg/ml                   0        =     no effect, i.e. growth was observed at the                                    highest concentration tested (100 μg/ml).                   ______________________________________                                    

In a first screening the drugs under investigation were tested againstthe following 11 fungi:

1. Microsporum canis (M. c. in the tables)

2. Ctenomyces mentagrophytes (Ct. m. in the tables)

3. Trichophyton rubrum (Tr. r. in the tables)

4. Phialopora verrucosa (Ph. v. in the tables)

5. Cryptococcus neoformans (Cr. n. in the tables)

6. Candida tropicalis (C. tr. in the tables)

7. Candida albicans (C. alb. in the tables)

8. Mucor species (Muc. in the tables)

9. Aspergillus fumigatus (A. f. in the tables)

10. Sporotrichum schenckii (Sp. s. in the tables)

11. Saprolegnia species (Sap. in the tables)

Bactericidal tests were performed on cultures on phenol red dextrosebroth Difco medium. The same decimal dilution techniques as describedherebefore were used. The inoculum consisted of a platinum loop (5 mm.diameter) from a 24 hour broth culture.

48 Hours after incubation, subcultures were made from each culture andfor the assessment of the bactericidal activity of the drugs underinvestigation the presence or absence of growth after 7 days incubationwas scored as described above.

The substances were tested against the following gram-positive bacilliand cocci:

1. Erysipelothrix insidiosa (E. ins. in the table),

2. Staphylococcus hemolyticus (Staph. in the table), and

3. Streptococcus pyogenes (Strept. in the table).

The results are summarized in Table II.

                                      Tables I                                    __________________________________________________________________________    ANTIFUNGAL ACTIVITY                                                            ##STR5##                                                                                         ANTIFUNGAL ACTIVITY                                                       Iso-                                                                              M. c.                                                                             Ct. m.                                                                            Tr. r.                                                                            Ph. v.                                                                            Cr. n.                                                                            C. tr.                                                                            C. alb.                                                                           Muc.                                                                             A. f.                                                                             Sp.                                                                               Sap.               Ar          R   mer (1) (2) (3) (4) (5) (6) (7) (8)                                                                              (9) (10)                                                                              (11)               __________________________________________________________________________    2,4-Cl.sub.2 --C.sub.6 H.sub.3                                                            C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ ++  +++ +++ o   +  +++ ++  ++                 2-Cl--C.sub.6 H.sub.4                                                                     C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   +   +   o   o  ++  +   ++                 2-CH.sub.3 --C.sub.6 H.sub.4                                                              C.sub.2 H.sub.5                                                                   A+B ++  +++ +++ +   +   +   o   o  ++  +   +                  4-CH.sub.3 --C.sub.6 H.sub.4                                                              C.sub.2 H.sub.5                                                                   A+B ++  +++ +++ +   +   +   o   o  +   o   +                  2,3,4-(Cl).sub.3 --C.sub.6 H.sub.2                                                        C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   +   +   ++  +  ++  ++  +                  2-Br--C.sub.6 H.sub.4                                                                     C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   +   +   +   o  +++ ++  ++                 2,3-(Cl).sub.2 --C.sub.6 H.sub.3                                                          C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   +   o   +   o  ++  +   +                  2-Cl, 4-F--C.sub.6 H.sub.3                                                                C.sub.2 H.sub.5                                                                   A+B + ++                                                                              +++ +++ +   ++  ++  +   o  +++ ++  ++                 4-Br--C.sub.6 H.sub.4                                                                     C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   +   +   +   o  ++  +   +                  3-Cl--C.sub.6 H.sub.4                                                                     C.sub.2 H.sub.5                                                                   A+B ++  +++ +++ +   +   o   +   o  +   +   +                  2-Cl, 4-Br--C.sub.6 H.sub.3                                                               C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   ++  ++  +   +  +++ ++  ++                 2,4-(Br).sub.2 --C.sub.6 H.sub.3                                                          C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ ++  +++ ++  o   +  +++ ++  ++                 4-OCH.sub.3 --C.sub.6 H.sub.4                                                             C.sub.2 H.sub.5                                                                   A+B ++  ++  +++ o   o   o   o   o  +   o   +                  2-thienyl   C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   o   +   o   o  +   o   +                  2-CH.sub.3, 4-Cl--C.sub.6 H.sub.3                                                         C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ ++  +++ ++  +   o  +++ ++  +++                                    ANTIFUNGAL ACTIVITY                                                           M. c.                                                                             Ct. m.                                                                            Tr. r.                                                                            Ph. v.                                                                            Cr. n.                                                                            C. tr.                                                                            C. alb.                                                                           Muc.                                                                             A. f.                                                                             Sp.                                                                               Sap.               Ar          R       (1) (2) (3) (4) (5) (6) (7) (8)                                                                              (9) (10)                                                                              (11)               __________________________________________________________________________    2-Cl, 4-OCH.sub.3 --C.sub.6 H.sub.3                                                       C.sub.2 H.sub.5                                                                   A+B +++ +++ +++  +  +   +   o   o  +++ +   +                  3,4,5-(Cl).sub.3 --C.sub.6 H.sub.2                                                        C.sub.2 H.sub.5                                                                   A+B ++  ++  +++ +   +   o   +   +  +   +   +                  2-naphthyl  C.sub.2 H.sub.5                                                                   A+B ++  +++ +++ +   +   o   o   +  +   +   +                  5-Cl-2-thienyl                                                                            C.sub.2 H.sub.5                                                                   A+B ++  +++ +++ +   +   +   o   o  ++  +   +                  2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                          nC.sub.3 H.sub.7                                                                  A+B +++ +++ +++ ++  +++ ++  +   ++ +++ ++  ++                 2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                          nC.sub.4 H.sub.9                                                                  A+B +++ ++  +++ ++  +++ ++  o   +  +++ +++ ++                 2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                          nC.sub.5 H.sub.11                                                                 A+B +++ +++ +++ +   +++ ++  ++  ++ ++  +++ ++                 2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                          nC.sub.6 H.sub.13                                                                 A+B +++ +++ +++ +   +++ o   ++  ++ +++ +++ +                  2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                          nC.sub.7 H.sub.15                                                                 A+B ++  +++ +++ +   +++ o   o   ++ ++  +++ +                  2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                          nC.sub.8 H.sub.17                                                                 A+B ++  +++ +++ +   ++  o   o   +  +   ++  +                  2-OCH.sub.3 -4-Cl--C.sub.6 H.sub.3                                                        C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   +   +   +   o  ++  +   +                  2,4,5-(Cl).sub.3 --C.sub.6 H.sub.2                                                        C.sub.2 H.sub.5                                                                   A+B +++ +++ +++ +   +   o   ++  ++ ++  +                      2,4-(Cl).sub.2 --C.sub.6 H.sub.4                                                          C.sub.2 H.sub.5                                                                   trans                                                                             +++ +++ +++ ++  ++  +   o   o  +++ ++  ++                 2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                          C.sub.2 H.sub.5                                                                   cis +++ +++ +++ ++  +++ +   ++  o  +++ ++  ++                 __________________________________________________________________________

    __________________________________________________________________________    BACTERIOSTATIC AND BACTERIOCIDAL ACTIVITY                                      ##STR6##                                                                                        Bacteriostatic activity                                                                   Bacteriocidal activity                         Ar         R   isomer                                                                            E. ins.                                                                           Staph.                                                                            Strept.                                                                           E. ins.                                                                           Staph.                                                                            Strept.                                __________________________________________________________________________    2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         C.sub.2 H.sub.5                                                                   A+B +++ ++  +++ ++  o   +++                                    2-Cl--C.sub.6 H.sub.4                                                                    C.sub.2 H.sub.5                                                                   A+B ++  +   o   ++  +   o                                      2-CH.sub.3 --C.sub.6 H.sub.4                                                             C.sub.2 H.sub.5                                                                   A+B ++  o   ++  o   o   o                                      4-CH.sub.3 --C.sub.6 H.sub.4                                                             C.sub.2 H.sub.5                                                                   A+B ++  +   ++  ++  o   ++                                     2,3,4-(Cl).sub.3 --C.sub.6 H.sub.2                                                       C.sub.2 H.sub.5                                                                   A+B + ++                                                                              ++  +++ +++ +   +++                                    2-Br--C.sub.6 H.sub.4                                                                    C.sub.2 H.sub.5                                                                   A+B ++  +   ++  ++  o   ++                                     2,3-(Cl).sub.2 --C.sub.6 H.sub.3                                                         C.sub.2 H.sub.5                                                                   A+B ++  +   ++  ++  o   ++                                     2-Cl, 4-F--C.sub.6 H.sub.3                                                               C.sub.2 H.sub.5                                                                   A+B ++  o   ++  ++  o   ++                                     4-Br--C.sub.6 H.sub.4                                                                    C.sub.2 H.sub.5                                                                   A+B ++  o   +   ++  o   +                                      3-Cl--C.sub.6 H.sub.4                                                                    C.sub.2 H.sub.5                                                                   A+B ++  o   ++  ++  o   ++                                     2-Cl, 4-Br--C.sub.6 H.sub.3                                                              C.sub.2 H.sub.5                                                                   A+B +++ +   ++  +++ +   ++                                     2,4-(Br).sub.2 --C.sub.6 H.sub.3                                                         C.sub.2 H.sub.5                                                                   A+B +++ +   ++  +++ +   ++                                     4-OCH.sub.3 --C.sub.6 H.sub.4                                                            C.sub.2 H.sub.5                                                                   A+B +   o   +   +   o   +                                      2-thienyl  C.sub.2 H.sub.5                                                                   A+B +   o   +   o   o   +                                      2-CH.sub.3, 4-Cl--C.sub.6 H.sub.3                                                        C.sub.2 H.sub.5                                                                   A+B +++ +   +   +++ +   +                                      2-Cl, 4-OCH.sub.3                                                                        C.sub.2 H.sub.5                                                                   A+B ++  +   ++  +   o   +                                      2-naphthyl C.sub.2 H.sub.5                                                                   A+B +++ +   ++  +   o   +                                      5-Cl-2-thienyl                                                                           C.sub.2 H.sub.5                                                                   A+B ++  +   ++  o   o   o                                      2-OCH.sub.3, 4-Cl--C.sub.6 H.sub.3                                                       C.sub.2 H.sub.5                                                                   A+B +   o   +   +   o   +                                      2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         nC.sub.3 H.sub.7                                                                  A+B +++ ++  +++ +++ +   +++                                    2,4-(Cl).sub.2 -- C.sub.6 H.sub.3                                                        nC.sub.4 H.sub.9                                                                  A+B +++ +++ +++ +++ +++ +++                                    2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         nC.sub.5 H.sub.11                                                                 A+B +++ ++  +++ +++ ++  +++                                    2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         nC.sub.6 H.sub.13                                                                 A+B +++ +++ +++ +++ ++  +++                                    2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         nC.sub.7 H.sub.15                                                                 A+B +++ +++ +++ +++ ++  +++                                    2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         nC.sub.8 H.sub.17                                                                 A+B +++ ++  +++ +++ ++  +++                                    2-OCH.sub.3 -4-Cl--C.sub.6 H.sub.3                                                       C.sub.2 H.sub.5                                                                   A+B ++  o   ++  ++  o   ++                                     2,4,5-(Cl).sub.3 --C.sub.6 H.sub.2                                                       C.sub.2 H.sub.5                                                                   A+B +++ +   +++ +++ +   +++                                    2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         C.sub.2 H.sub.5                                                                   trans                                                                             +++ +   ++  +++ o   +                                      2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                         C.sub.2 H.sub.5                                                                   cis +++ ++  ++  ++  o   +                                      3,4,5-(Cl).sub.3 --C.sub.6 H.sub.2                                                       C.sub.2 H.sub.5                                                                   A+B +++ ++  +++ ++  +   ++                                     __________________________________________________________________________

in view of the aforementioned antifungal and antibacterial activitiesthis invention provides valuable compositions comprising the subject1,3-dioxolan-2-ylmethyl imidazoles (I) or the acid addition saltsthereof as the active ingredient in a solvent or a solid, semi-solid orliquid diluent or carrier, and, in addition, it provides an effectivemethod of combatting fungus or bacterial growth by use of an effectiveanti-fungal or anti-bacterial amount of such ketals (I) or saltsthereof. The subject compounds can be used in suitable solvents ordiluents, in the form of emulsions, suspensions, dispersions orointments, on suitable solid or semi-solid carrier substances, inordinary or synthetic soaps, detergents or dispersion media, if desired,together with other compounds having arachnicidal, insecticidal,fungicidal and/or bactericidal effects, or together with inactiveadditives.

Solid carrier substances which are suitable for the preparation ofcompositions in powder form include various inert, porous and pulverousdistributing agents of inorganic or organic nature, such as, forexample, tricalcium phosphate, calcium carbonate, in the form ofprepared chalk or ground limestone, kaolin, bole, bentonite, talcum,kieselguhr and boric acid; powdered cork, sawdust, and other finepulverous materials of vegetable origin are also suitable carriersubstances.

The active ingredient is mixed with these carrier substances, forexample, by being ground therewith; alternatively, the inert carriersubstance is impregnated with a solution of the active component in areadily volatile solvent and the solvent is thereafter eliminated byheating or by filtering with suction at reduced pressure. By addingwetting and/or dispersing agents, such pulverous preparations can alsobe made readily wettable with water, so that suspensions are obtained.

Inert solvents used for the production of liquid preparations shouldpreferably not be readily inflammable and should be as far as possibleodorless and as far as possible non-toxic to warm-blooded animals orplants in the relevant surroundings. Solvents suitable for this purposeare high-boiling oils, for example, of vegetable origin, andlower-boiling solvents with a flash point of at least 30° C., such as,for example, polyethylene glycols, isopropanol, dimethylsulfoxide,hydrogenated naphthalenes and alkylated naphthalenes. It is, of cours,also possible to use mixtures of solvents. Solutions can be prepared inthe usual way, if necessary, with assistance of solution promotors.Other liquid forms which can be used consist of emulsions or suspensionsof the active compound in water or suitable inert solvents, or alsoconcentrates for preparing such emulsions, which can be directlyadjusted to the required concentration. For this purpose, the activeingredient is, for example, mixed with a dispersing or emulsifyingagent. The active component can also be dissolved or dispersed in asuitable inert solvent and mixed simultaneously or subsequently with adispersing or emulsifying agent.

It is also possible to use semi-solid carrier substances of a creamointment, paste or waxlike nature, into which the active component canbe incorporated, if necessary, with the aid of solution promotors and/oremulsifiers. Vaseline and other cream bases are examples of semi-solidcarrier substances.

Furthermore, it is possible for the active component to be used in theform of aerosols. For this purpose, the active component is dissolved ordispersed, if necessary, with the aid of suitable inert solvents ascarrier liquids, such as difluorodichloromethane, which at atmosphericpressure boils at a temperature lower than room temperature, or in othervolatile solvents. In this way, solutions under pressure are obtainedwhich, when sprayed, yield aerosols which are particularly suitable forcontrolling or combatting fungi and bacteria, e.g., in closed chambersand storage rooms, and for application to vegetation for eradicating orfor preventing infections by fungi or bacteria.

The subject compounds and compositions thereof can be applied byconventional methods. For example, a fungus or bacterial growth or amaterial to be treated or to be protected against attack by fungus orbacterium can be treated with the subject compounds and the compositionsthereof by dusting, sprinkling, spraying, brushing, dipping, smearing,impregnating or other suitable means.

When the subject compounds are employed in combination with suitablecarriers, e.g., in solution, suspension, dust, powder, ointment,emulsion, and the like forms, a high activity over a very high range ofdilution is observed. For example, concentrations of the activeingredient ranging from 0.1-10 percent by weight, based on the weight ofcomposition employed, have been found effective in combatting fungi orbacteria. Of course, higher concentrations may also be employed aswarranted by the particular situation.

The following examples are intended to illustrate, but not to limit, thescope of the present invention. Unless otherwise stated, all parts areby weight.

EXAMPLE I

A mixture of 13.5 parts of 1,2-butanediol, 37.5 parts of2-bromo-1-(2,4-dichlorophenyl)ethanone, 2 parts of4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts ofmethylbenzene is stirred and refluxed for 24 hours with water-separator.The reaction mixture is cooled, washed twice with a sodium bicarbonatesolution, dried, filtered and evaporated. The residue is distilled,yielding 38 parts (80%) ofA+B-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane; bp.125°-130° C. at 0.1 mm. pressure.

EXAMPLE II

Following the procedure of Example I and using equivalent amounts of theappropriate starting materials, the following dioxolanes are prepared:

    ______________________________________                                         ##STR7##                                                                     R       R.sup.1     boiling point                                             ______________________________________                                        C.sub.2 H.sub.5                                                                       2-Cl        97°-99° C. at 0.05 mm. pressure             C.sub.2 H.sub.5                                                                       2-CH.sub.3  86°-88° C. at 0.05 mm. pressure             C.sub.2 H.sub.5                                                                       4-CH.sub.3  100° C. at 0.05 mm. pressure                       C.sub.2 H.sub.5                                                                       2-Br        114°-115° C. at 0.05 mm. pressure           C.sub.2 H.sub.5                                                                       3-Cl        140° C. at 0.6 mm. pressure                        C.sub.2 H.sub.5                                                                       2-Cl, 4-Br    --                                                      C.sub.2 H.sub.5                                                                       4-OCH.sub.3 122° C. at 0.15 mm. pressure                       C.sub.2 H.sub.5                                                                       3,4,5-(Cl).sub.3                                                                          135° C. at 0.05 mm. pressure                       nC.sub.3 H.sub.7                                                                      2,4-(Cl).sub.2                                                                            102°-125° C. at 0.05 mm. pressure           nC.sub.4 H.sub.9                                                                      2,4-(Cl).sub.2                                                                            137°-139° C. at 0.05 mm. pressure           nC.sub.5 H.sub.11                                                                     2,4-(Cl).sub.2                                                                            140°-145° C. at 0.03 mm. pressure           nC.sub.6 H.sub.13                                                                     2,4-(Cl).sub.2                                                                            163°-170° C. at 0.1 mm. pressure            nC.sub.7 H.sub.15                                                                     2,4-(Cl).sub.2                                                                            160°-165° C. at 0.05 mm. pressure           nC.sub.8 H.sub.17                                                                     2,4-(Cl).sub.2                                                                            180°-190° C. at 0.05 mm.                    ______________________________________                                                            pressure                                              

EXAMPLE III

To a stirred solution of 120 parts of 1-(2,3-dichlorophenyl)-1-ethanonein 240 parts of butanol are added dropwise 101 parts of bromine at roomtemperature. After stirring for 1 hour at room temperature, there areadded successively 42 parts of 1,2-ethanediol, 540 parts of anhydrousbenzene and 4 parts of 4-methylbenzenesulfonic acid. The whole isstirred and refluxed overnight with water-separator. The reactionmixture is evaporated and the residue is dissolved in2,2'-oxybispropane. The solution is washed with a diluted sodiumhydroxide solution and three times with water, dried, filtered andevaporated. The residue is distilled, yielding 96.6 parts (49%) of2-(bromomethyl)-2-(2,3-dichlorophenyl)-1,3-dioxolane; bp. 135°-137° C.at 0.1 mm. pressure.

EXAMPLE IV

Following the procedure of Example III and using an equivalent amount ofan appropriate 1-aryl-1-ethanone in place of the1-(2,3-dichlorophenyl)-1-ethanone used therein the following2-aryl-2-(bromomethyl)-1,3-dioxolanes are prepared:

2-(bromomethyl)-2-(4-chloro-2-methylphenyl)-1,3-dioxolane; and

2-(bromomethyl)-2-(2-chloro-4-methoxyphenyl)-1,3-dioxolane; mp. 53° C.

EXAMPLE V

To a stirred solution of 74.4 parts of2-bromo-1-(2-naphthalenyl)-1-ethanone in 240 parts of butanol are addedsuccessively 3 parts of 4-methylbenzenesulfonic acid and 270 parts ofbenzene. Then there are added dropwise 28 parts of 1,2-butanediol. Uponcompletion, stirring is continued overnight at reflux temperature. Thereaction mixture is evaporated. The residue is dissolved in2,2'-oxybispropane and the solution is stirred with a diluted sodiumhydroxide solution. The layers are separated and the aqueous phase isextracted with 2,2'-oxybispropane. The extract is neutralized withwater, dried, filtered and evaporated. The oily residue is crystallizedfrom methanol. The product is filtered off and recrystallized frommethanol, yielding 41 parts of2-(bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64° C.

EXAMPLE VI

A mixture of 13 parts of 1,2-butanediol, 31.2 parts of2-(bromomethyl)-2-(2,3-dichlorophenyl)-1,3-dioxolane, 5 parts of4-methylbenzenesulfonic acid, 40 parts of 1-butanol and 225 parts ofdimethylbenzene is stirred and refluxed for 1 week. The reaction mixtureis cooled, washed with a potassium carbonate solution, dried, filteredand evaporated. The residue is distilled, yielding 23 parts (67%) of(A+B)-2-(bromomethyl)-2-(2,3-dichlorophenyl)-4-ethyl-1,3-dioxolane; bp.131°-133° C. at 0.1 mm. pressure.

EXAMPLE VII

Following the procedure of Example VI and using equivalent amounts ofthe appropriate starting materials, the following dioxolanes areprepared:

(A+B)-2-(bromomethyl)-4-ethyl-2-(2,3,4-trichlorophenyl)-1,3-dioxolane;bp. 145° C. at 0.1 mm. pressure;

(A+B)-2-(bromomethyl)-2-(4-chloro-2-methylphenyl)-4-ethyl-1,3-dioxolane;bp. 118° C. at 0.15 mm. pressure;

(A+B)-2-(bromomethyl)-2-(2-chloro-4-methoxyphenyl)-4-ethyl-1,3-dioxolane;bp. 142°-144° C. at 0.3 mm. pressure; and

(A+B)-2-(bromomethyl)-4-ethyl-2-(2-naphthalenyl)-1,3-dioxolane as aresidue.

EXAMPLE VIII

To a stirred and warm solution of 6.5 parts of 1,2-butanediol, 13 partsof 1-(4-chloro-2-methoxyphenyl)ethanone, 40 parts of 1-butanol are addeddropwise (slowly) 5.7 parts of bromine at about 40° C. After stirringfor 30 minutes, there are added 2 parts of 4-methylbenzenesulfonic acidand 225 parts of methylbenzene and the whole is stirred and refluxedovernight with water-separator. The reaction mixture is cooled, washedwith a potassium carbonate solution, dried, filtered and evaporated. Theresidue is distilled, yielding 17 parts (63%)of(A+B)-2-(bromomethyl)-2-(4-chloro-2-methoxyphenyl)-4-ethyl-1,3-dioxolane;bp. 135°-140° C. at 0.3 mm. pressure.

EXAMPLE IX

To a stirred mixture of 9.2 parts of 1,2-butanediol, 22.3 parts of1-(2,4,5-trichlorophenyl)ethanone and 56 parts of 1-butanol are addeddropwise 8.25 parts of bromine at about 40° C. After stirring for 1 hourat room temperature, there are added 2 parts of 4-methylbenzenesulfonicacid and 107 parts of methylbenzene and the whole is stirred andrefluxed overnight with water-separator. The reaction mixture is cooled,washed with a potassium carbonate solution, dried, filtered andevaporated. The residue is distilled, yielding 10 parts of(A+B)-2-(bromomethyl)-4-ethyl-2-(2,4,5-trichlorophenyl)-1,3-dioxolane;bp. 145° C. at 0.2 mm. pressure.

EXAMPLE X

16 Parts of(A+B)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane areseparated by column-chromatography over silica gel using a mixture ofhexane and trichloromethane (95:5 by volume) as eluent.

The first fraction (A-isomer) is collected and the eluent is evaporated,yielding 5.5 parts of(A)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane as aresidue.

The second fraction (B-isomer) is collected and the eluent isevaporated, yielding 9 parts of(B)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane as aresidue.

EXAMPLE XI

To a stirred sodium methoxide solution, prepared starting from 3.8 partsof sodium in 40 parts of methanol, are added 11 parts of 1H-imidazoleand 225 parts of N,N-dimethylformamide. The methanol is distilled offtill internal temperature of 150° C. Then there are added 19 parts of(A+B)-2-(bromomethyl)-2-(2,4-dichlorophenyl-4-ethyl-1,3-dioxolane andthe whole is stirred and refluxed for 1 hour. The reaction mixture isallowed to cool to room temperature and poured onto water. The productis extracted three times with 1,1'-oxybisethane. The combined extractsare washed with water, dried, filtered and evaporated. The residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and 1% of methanol as eluent. The first fraction iscollected and the eluent is evaporated. The residue is converted intothe nitrate salt in 2,2'-oxybispropane. The salt is filtered off andcrystallized from a mixture of 2-propanol and 2,2'-oxybispropane,yielding 12 parts (56%) of(A+B)-1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 149.1° C.

EXAMPLE XII

To a stirred sodium methoxide solution, prepared starting from 2.8 partsof sodium in 40 parts of methanol, are added 8 parts of 1H-imidazole and225 parts of N,N-dimethylformamide. The methanol is distilled off tillinternal temperature of 150° C. Then there are added 30 parts of(A+B)-2-(4-bromo-2-chlorophenyl)-2-(bromomethyl)-4-ethyl-1,3-dioxolaneand stirring is continued for 1 hour at reflux temperature. The reactionmixture is cooled and poured onto water. The product is extracted twicewith 2,2'-oxybispropane. The combined extracts are washed with water,dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 2% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The residue is converted intothe nitrate salt in 2,2'-oxybispropane. The salt is filtered off andcrystallized from a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane, yielding 8.5 parts (26%) of (A+B)-1-[2-(4-bromo-2-chlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 162.2° C.

EXAMPLE XIII

Following the procedure of Example XII and using equivalent amounts ofthe appropriate starting materials, the following imidazole acidaddition salts are prepared:

    ______________________________________                                         ##STR8##                                                                     Ar            R       Acid Salt  Melting Point                                ______________________________________                                        2-Cl--C.sub.6 H.sub.4                                                                       C.sub.2 H.sub.5                                                                       HNO.sub.3  147.6° C.                             2-CH.sub.3 --C.sub.6 H.sub.4                                                                C.sub.2 H.sub.5                                                                       HNO.sub.3  117.5° C.                             4-CH.sub.3 --C.sub.6 H.sub.4                                                                C.sub.2 H.sub.5                                                                       HNO.sub.3  172.7° C.                             2,3,4-(Cl).sub.3 --C.sub.6 H.sub.2                                                          C.sub.2 H.sub.5                                                                       HNO.sub.3  176.4° C.                             2-Br--C.sub.6 H.sub.4                                                                       C.sub.2 H.sub.5                                                                       HNO.sub.3  135.3° C.                             2,3-(Cl).sub.2 --C.sub.6 H.sub.3                                                            C.sub.2 H.sub.5                                                                       HNO.sub.3  140.3° C.                             3-Cl--C.sub.6 H.sub.4                                                                       C.sub.2 H.sub.5                                                                       HNO.sub.3  151.6° C.                             4-OCH.sub.3 --C.sub.6 H.sub.4                                                               C.sub.2 H.sub.5                                                                       HNO.sub.3  157.1° C.                             2-CH.sub.3 -4-Cl--C.sub.6 H.sub.3                                                           C.sub.2 H.sub.5                                                                       HNO.sub.3  126.8° C.                             2-Cl-4-OCH.sub.3 --C.sub.6 H.sub. 3                                                         C.sub.2 H.sub.5                                                                       HNO.sub.3  117.7° C.                             3,4,5-(Cl).sub.3 --C.sub.6 H.sub.2                                                          C.sub.2 H.sub.5                                                                       HNO.sub.3  195.8° C.                             2-naphthyl    C.sub.2 H.sub.5                                                                       HNO.sub.3  195.1° C.                             2-OCH.sub.3 -4-Cl--C.sub.6 H.sub.3                                                          C.sub.2 H.sub.5                                                                       HNO.sub.3  131.8° C.                             2,4,5-(Cl).sub.3 --C.sub.6 H.sub.2                                                          C.sub.2 H.sub.5                                                                       HNO.sub.3  180.1° C.                             2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                            nC.sub.3 H.sub.7                                                                      HNO.sub.3  119.2° C.                             2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                            nC.sub.4 H.sub.9                                                                      HNO.sub.3  113.1° C.                             2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                            nC.sub.5 H.sub.11                                                                     HNO.sub.3  128.3° C.                             2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                            nC.sub.6 H.sub.13                                                                     HNO.sub.3  99.4° C.                              2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                            nC.sub.7 H.sub.15                                                                     2(COOH).sub.2                                                                            131° C.                               2,4-(Cl).sub.2 --C.sub.6 H.sub.3                                                            nC.sub.8 H.sub.17                                                                     2(COOH).sub.2                                                                            132.8° C.                             ______________________________________                                    

example xiv

a mixture of 12.5 parts of 1,2-butanediol, 19 parts of1-(2-chloro-4-fluorophenyl)-2-(1H-imidazol-1-yl)ethanone hydrochloride,16 parts of 4-methylbenzenesulfonic acid, 40 parts of 1-butanol and 225parts of dimethylbenzene is stirred and refluxed for 6 days withwater-separator. After cooling, the reaction mixture is filtered and thefiltrate is washed with a diluted sodium hydroxide solution and withwater. After the addition of 2,2'-oxybispropane, the whole is acidifiedwith a nitric acid solution. The formed nitrate salt is filtered off andcrystallized from a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane, yielding 5.7 parts (22%) of(A+B)-1-[2-(2-chloro-4-fluorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 132.4° C.

EXAMPLE XV

Following the procedure of Example XIV and using equivalent amounts ofthe appropriate starting materials, the following imidazole acidaddition salts are prepared:

(A+B)-1-[2-(4-bromophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 194.7° C.;

(a+b)-1-[2-(2,4-dibromophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 149.7° C.;

(a+b)-1-[4-ethyl-2-(2-thienyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 135.4° C.; and

(A+B)-1-[2-(5-chloro-2-thienyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 164.3° C.

EXAMPLE XVI

To a stirred solution methoxide solution, prepared starting from 1.8parts of sodium in 20 parts of methanol, are added 5.4 parts of1H-imidazole and 112 parts of N,N-dimethylformamide. The methanol isdistilled off till internal temperature of 130° C. Then there are added9 parts of(B)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane and thewhole is stirred and refluxed for 1 hour. The reaction mixture is cooledand poured onto water. The product is extracted three times with1,1'-oxybisethane. The combined extracts are washed with water, dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture of benzene andethanol (95:5 by volume) as eluent. The pure fractions are collected andthe eluent is evaporated. The residue is converted into the nitrate saltin 2-propanol. The salt is filtered and dried, yielding 3.7 parts (36%)oftrans-1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 164° C.

EXAMPLE XVII

Following the procedure of Example XVI there is preparedcis-1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazolenitrate; mp. 160.2° C. by the reaction of imidazole withcis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane.

I claim:
 1. A chemical compound selected from the group consisting of animidazole derivative having the formula ##STR9## and the therapeuticallyacceptable acid addition salts thereof, wherein: R is alkyl having from2 to 10 carbon atoms; andAr is a member selected from the groupconsisting of phenyl, substituted phenyl, thienyl, halothienyl andnaphthalenyl, and wherein said substituted phenyl is phenyl having from1 to 3 substituents independently selected from the group consisting ofhalo, lower alkyl, lower alkyloxy, nitro and cyano.
 2. A chemicalcompound selected from the group consisting of1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand the therapeutically acceptable acid addition salts thereof.
 3. Achemical compound selected from the group consisting ofcis-1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand the therapeutically acceptable acid addition salts thereof.
 4. Achemical compound selected from the group consisting of1-[2-(2-chloro-4-fluorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand the therapeutically acceptable acid addition salts thereof.
 5. Achemical compound selected from the group consisting of1-[2-(4-bromo-2-chlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand the therapeutically acceptable acid addition salts thereof.
 6. Acomposition for combatting the growth of a microorganism selected fromthe group consisting of fungus and bacterium comprising an inert carriermaterial and as an active ingredient an effective amount of a compoundselected from the group consisting of an imidazole derivative having theformula: ##STR10## and the therapeutically active acid addition saltsand stereochemical optical isomeric forms thereof, wherein:R is alkylhaving from 2 to 10 carbon atoms; and Ar is a member selected from thegroup consisting of phenyl, substituted phenyl, thienyl, halothienyl andnaphthalenyl, and wherein said substituted phenyl is phenyl having from1 to 3 substituents independently selected from the group consisting ofhalo, lower alkyl, lower alkyloxy, nitro and cyano.
 7. A composition forcombatting the growth of a microorganism selected from the groupconsisting of fungus and bacterium comprising an inert carrier materialand as an active ingredient an effective amount of a compound selectedfrom the group consisting of1-[2-(4-bromo-2-chlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand the therapeutically active acid addition salts thereof.
 8. Acomposition for combatting the growth of a microorganism selected fromthe group consisting of fungus and bacterium comprising an inert carriermaterial and as an active ingredient an effective amount of a compoundselected from the group consisting of1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand the therapeutically active acid addition salts thereof.
 9. Acomposition for combatting the growth of a microorganism selected fromthe group consisting of fungus and bacterium comprising an inert carriermaterial and as an active ingredient an effective amount of a compoundselected from the group consisting of1-[2-(2-chloro-4-fluorophenyl)-4-ethyl-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand the therapeutically active acid addition salts thereof.